DESCRIPTION: Urinary catheters are placed in one of four hospitalized patients. One in five catheterized patients develops catheter associated bacteriuria (CAB) that often progresses to catheter associated urinary tract infection (CAUTI). Patients with CAUTI have a 2.8 fold increase in mortality and account for 40% of all hospital acquired infections. Patients with CAB/CAUTI also provide a huge reservoir of drug resistant organisms in hospitals. The basic biological mechanisms of CAB and CAUTI are poorly understood. In particular the role of urinary host defense factors is poorly defined. Tamm-Horsfall Protein (uromodulin, THP) is urine's most abundant protein and has been shown to bind easily to a variety of surfaces and substances. THP has been demonstrated to act as a host defense factor against urinary tract infection (UTI), by binding bacteria in urine and clearing them before they can adhere to the urinary epithelium. The role of THP, if any, in CAB/CAUTI has not been studied. In this R21 application, we propose to test a new hypothesis that THP, which normally helps prevent UTI in the absence of a catheter, plays the opposite role of promoting UTI in the presence of a urinary catheter. THP binds to the catheter surface to form a conditioning layer. Bacteria adhere to THP on the catheter surface and form a biofilm under which they multiply to establish a reservoir that serves as a continuing source of bacteria in urine. Using in-vitro and animal studies, we will address 4 key questions: a) Does THP bind to urinary catheters? b) Does THP promote binding of bacteria to urinary catheters? c) Does THP facilitate formation of bacterial biofilm on urinary catheters? and d) Does the absence of THP increase or ecrease the risk of CAUTI? This proposal will test a new hypothesis about the role of THP in the pathogenesis of CAB and CAUTI. The data generated will point towards new strategies to combat CAUTI. PUBLIC HEALTH RELEVANCE: Infection of urinary catheters is a major problem in hospitals and nursing homes. The infected catheter makes the patient sick and is a source of infection for other patients. This proposal will research how urinary catheters get infected and will point towards preventive strategies against catheter infection.